Bottom Line:
Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation.We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis.These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.

ABSTRACTOsteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Mentions:
We first asked whether LP533401 could prevent ovariectomy–induced bone loss. Six week–old sham–operated or ovariectomized female C57Bl6/J mice were fed once daily with either vehicle or LP533401 at doses ranging from 1 to 250 mg per kg body weight per day from day 1 to 28 post–ovariectomy (Fig. 2a and Supplementary Fig. 3a). Osteoclast surface and serum deoxypyridinoline (Dpd) levels, a marker of bone resorption, were higher in ovariectomized mice, regardless of their treatment, than in sham–operated animals and, as a result, vehicle–treated ovariectomized mice developed a low bone mass (osteopenia) (Fig. 2a and Supplementary Fig. 3b). In contrast, mice treated with 250, 100 or even 10 mg per kg body weight per day of LP533401 had a higher bone mass than that of vehicle–treated ovariectomized mice (Fig. 2a). Consistent with the influence of GDS on osteoblast proliferation and bone formation, this increase in bone mass in the LP533401–treated ovariectomized mice was secondary to a major increase in bone formation parameters such as osteoblast numbers, bone formation rate, and osteocalcin serum levels (Fig. 2a and Supplementary Fig. 3c–d). We verified that although serum serotonin levels were decreased in a dose–dependent manner, brain serotonin content remained unaffected in LP533401–treated ovariectomized mice (Fig. 2b). These results established that LP533401 could prevent the development of ovariectomy–induced osteoporosis in the mouse. That a favorable effect on bone formation parameters is observed with a relatively small reduction in circulating serotonin levels (~30%) echoes what is observed in genetic model of decreased circulating serotonin levels. In that case the increase in bone formation parameters observed in heterozygous mutant mice is not statistically different from the one seen in homozygous mutant mice2. This suggests that there is a threshold for the reduction in serum serotonin levels beyond which the skeletal response is marginally increased.

Mentions:
We first asked whether LP533401 could prevent ovariectomy–induced bone loss. Six week–old sham–operated or ovariectomized female C57Bl6/J mice were fed once daily with either vehicle or LP533401 at doses ranging from 1 to 250 mg per kg body weight per day from day 1 to 28 post–ovariectomy (Fig. 2a and Supplementary Fig. 3a). Osteoclast surface and serum deoxypyridinoline (Dpd) levels, a marker of bone resorption, were higher in ovariectomized mice, regardless of their treatment, than in sham–operated animals and, as a result, vehicle–treated ovariectomized mice developed a low bone mass (osteopenia) (Fig. 2a and Supplementary Fig. 3b). In contrast, mice treated with 250, 100 or even 10 mg per kg body weight per day of LP533401 had a higher bone mass than that of vehicle–treated ovariectomized mice (Fig. 2a). Consistent with the influence of GDS on osteoblast proliferation and bone formation, this increase in bone mass in the LP533401–treated ovariectomized mice was secondary to a major increase in bone formation parameters such as osteoblast numbers, bone formation rate, and osteocalcin serum levels (Fig. 2a and Supplementary Fig. 3c–d). We verified that although serum serotonin levels were decreased in a dose–dependent manner, brain serotonin content remained unaffected in LP533401–treated ovariectomized mice (Fig. 2b). These results established that LP533401 could prevent the development of ovariectomy–induced osteoporosis in the mouse. That a favorable effect on bone formation parameters is observed with a relatively small reduction in circulating serotonin levels (~30%) echoes what is observed in genetic model of decreased circulating serotonin levels. In that case the increase in bone formation parameters observed in heterozygous mutant mice is not statistically different from the one seen in homozygous mutant mice2. This suggests that there is a threshold for the reduction in serum serotonin levels beyond which the skeletal response is marginally increased.

Bottom Line:
Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation.We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis.These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Affiliation:
Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.

ABSTRACTOsteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.